A Case of Transient Neonatal Diabetes Mellitus Attributable to a Nonspecific Mutation in the ABCC8 Gene

Neonatal diabetes mellitus (NDM) is defined as hyperglycemia that persists for more than 2 weeks and requires insulin therapy. NDM principally occurs before 6 months of age. Transient NDM (TNDM) is a clinical form of NDM that persists for a median of 12 weeks and resolves completely by 18 months. However, it may relapse as type 2 DM during early adulthood. The major causes of TNDM are mutations in chromosome 6q24 or the KCNJ11 or ABCC8 genes; the latter encode the two subunits of the pancreatic adenosine triphosphate (ATP)-sensitive potassium channel (KATP-channel). This condition responds well to oral sulfonylurea therapy. Herein, we report a neonate who was small for gestational age and exhibited TNDM symptoms. Genetic analysis revealed a nonspecific mutation in ABCC8; he was successfully treated with oral sulfonylurea.

Familial hyperinsulinaemic hypoglycaemia with epileptic syndrome, cognitive impairment and detected mutation of the ABCC 8 (SUR1) gene: a case report

Hyperinsulinaemic hypoglycaemia (HH) occurs as a consequence of unregulated insulin secretion from pancreatic beta cells. It is the most common cause of severe and prolonged hypoglycemia in newborns. HH is a major risk factor for brain damage and subsequent neurological disability, which is why the identification, rapid diagnosis, and timely treatment of patients with HH are essential for the prevention of brain damage. The present case gives a brief description of a patient with congenital HH with an established mutation in the ABCC8 gene encoding the SUR1 subunit of the K-ATP channel. The genealogical tree, the clinical picture, the diagnostic cascade, the neurological consequences and their development in dynamics are considered, with special emphasis on the epileptic syndrome and mental status. Advances in molecular genetics, radiological imaging techniques, conservative treatment, or laparoscopic surgery may completely change the clinical approach to children with severe congenital forms of HH.

Genome-edited zebrafish model of ABCC8 loss-of-function disease

KATP channel gain- (GOF) and loss-of-function (LOF) mutations underlie human neonatal diabetes mellitus (NDM) and hyperinsulinism (HI), respectively. Genetically modified mice with transgenic overexpression of GOF mutations recapitulate many features of human NDM but, importantly, there are currently no gene knock-in mouse models of GOF mutations. Moreover, while transgenic mice expressing incomplete KATP LOF do reiterate mild hyperinsulinism, KATP knockout animals do not exhibit persistent hyperinsulinism. We have shown that islet excitability and glucose homeostasis are regulated by identical KATP channels in zebrafish. SUR1 truncation mutation (K499X) was introduced into the abcc8 gene to explore the possibility of using zebrafish for modeling human NDM and HI. Patch-clamp analysis confirmed complete absence of channel activity in β-cells from K499X (SUR1-/-) fish. No difference in random blood glucose was detected in heterozygous SUR1+/- fish, nor in homozygous SUR1-/- fish, mimicking findings in SUR1 knockout mice. Mutant fish did however, demonstrate impaired glucose tolerance, similar to partial LOF mouse models. In paralleling features of mammalian diabetes and hyperinsulinism resulting from equivalent gain- or loss-of-function mutations, these gene-edited animals provide valid zebrafish models of KATP LOF driven-dependent pancreatic disease.

Clinical and Genetic Characteristics of ABCC8 Nonneonatal Diabetes Mellitus: A Systematic Review

Objectives. Diabetes mellitus (DM) is a major chronic metabolic disease in the world, and the prevalence has been increasing rapidly in recent years. The channel of KATP plays an important role in the regulation of insulin secretion. The variants in ABCC8 gene encoding the SUR1 subunit of KATP could cause a variety of phenotypes, including neonatal diabetes mellitus (ABCC8-NDM) and ABCC8-induced nonneonatal diabetes mellitus (ABCC8-NNDM). Since the features of ABCC8-NNDM have not been elucidated, this study is aimed at concluding the genetic features and clinical characteristics. Methods. We comprehensively reviewed the literature associated with ABCC8-NNDM in the following databases: MEDLINE, PubMed, and Web of Science to investigate the features of ABCC8-NNDM. Results. Based on a comprehensive literature search, we found that 87 probands with ABCC8-NNDM carried 71 ABCC8 genetic variant alleles, 24% of whom carried inactivating variants, 24% carried activating variants, and the remaining 52% carried activating or inactivating variants. Nine of these variants were confirmed to be activating or inactivating through functional studies, while four variants (p.R370S, p.E1506K, p.R1418H, and p.R1420H) were confirmed to be inactivating. The phenotypes of ABCC8-NNDM were variable and could also present with early hyperinsulinemia followed by reduced insulin secretion, progressing to diabetes later. They had a relatively high risk of microvascular complications and low prevalence of nervous disease, which is different from ABCC8-NDM. Conclusions. Genetic testing is essential for proper diagnosis and appropriate treatment for patients with ABCC8-NNDM. And further studies are required to determine the complex mechanism of the variants of ABCC8-NNDM.

Novel Compound Heterozygous Variants of the ABCC8 Gene Warrant Identification of Pancreatic Histology in Infant with Diazoxide-unresponsive Congenital Hyperinsulinism

Congenital hyperinsulinism (CHI) is characterized by dysregulated insulin secretion, resulting in severe hypoglycemia. Mutations in the ABCC8 and KCNJ11 genes encoding KATP channels in beta cells of the pancreas are common among patients with CHI. Autosomal recessive CHI with diffuse involvement is the most common type of CHI among Saudi patients. It is relatively common for patients with autosomal recessive CHI to be medically unresponsive and undergo pancreatectomy. In this case report, we describe novel compound heterozygous variants in the ABCC8 gene in a Saudi infant that caused diazoxide-unresponsive CHI. The variants included a monoallelic paternally inherited variant that has been previously reported to cause a focal form of CHI and a maternally inherited variant of unknown significance (VUS). The severity of CHI in this patient was mild over the one-year follow-up period, with a near-optimal glycemic response on a low dose of octreotide. We suspected an atypical subtype of histological involvement in the patient. In this report, we highlight the phenotypic spectrum of novel compound heterozygous variants in a patient with CHI and consider that the report can help establish the pathogenicity of the VUS.

Genotyping of ABCC8, KCNJ11, and HADH in Iranian Infants with Congenital Hyperinsulinism

Background. Congenital hyperinsulinism (CHI) is a heterogeneous disease with various underlying genetic causes. Among different genes considered effective in the development of CHI, ABCC8, KCNJ11, and HADH genes are among the important genes, especially in a population with a considerable rate of consanguineous marriage. Mutational analysis of these genes guides clinicians to better treatment and prediction of prognosis for this rare disease. The present study aimed to evaluate genetic variants in ABCC8, KCNJ11, and HADH genes as causative genes for CHI in the Iranian population. Methods. The present case series took place in Mashhad, Iran, within 11 years. Every child who had a clinical phenotype and confirmatory biochemical tests of CHI enrolled in this study. Variants in ABCC8, KCNJ11, and HADH genes were analyzed by the polymerase chain reaction and sequencing in our patients. Results. Among 20 pediatric patients, 16 of them had variants in ABCC8, KCNJ11, and HADH genes. The mean age of genetic diagnosis was 18.6 days. A homozygous missense (c.2041-21G > A) mutation in the ABCC8 gene was seen in three infants. Other common variants were frameshift variants (c.3438dup) in the ABCC8 gene and a missense variant (c.287-288delinsTG) in the KCNJ11 gene. Most of the variants in our population were still categorized as variants of unknown significance and only 7 pathogenic variants were present. Conclusion. Most variants were located in the ABCC8 gene in our population. Because most of the variants in our population are not previously reported, performing further functional studies is warranted.

Persistent Hyperinsulinemic Hypoglycemia in Infancy-A Case Report

Persistent hyperinsulinemic hypoglycemia of infancy (PHHI) is one of the commonest reasons for severe, intractable hypoglycemia in neonates. Dysregulated insulin secretion is the major underlying pathogenesis which results in hyperinsulinemia, hypoketonemia and hypofatty acidemia. The management is extremely complicated. Early diagnosis and aggressive management of hyperinsulinemic hypoglycemia is essential for prevention of hypoglycemia induced neuronal injury. Here we describe a baby diagnosed as PHHI who was unresponsive to medical management with diazoxide and underwent near total pancreatectomy. Genetic work up revealed a homozygous termination mutation in ABCC8 gene at amino acid position 1452 with heterozygosity in both parents.